The global mortality of chronic obstructive pulmonary disease (COPD) continues to rise. Unfortunately, the predominant techniques for assessing its progression exhibit important shortcomings. Spirometry, the most commonly used surrogate marker in clinical trials, offers only global indications of functional alteration, and it has encountered substantial difficulty in sensitively and specifically assessing the heterogeneous abnormalities associated with COPD. While computed tomography (CT) produces excellent high-resolution images of key regional abnormalities, most of these images are anatomic and only indirectly related to physiology, and the exposure of patients to ionizing radiation can proscribe its use in longitudinal studies. To address these drawbacks, this project aims to refine and test a hyperpolarized gas magnetic resonance imaging (HP gas MRI) approach for the measurement of several important aspects of COPD pathophysiology in human subjects. The proposed method will allow for the simultaneous obtainment of three regional parameters that together offer a nuanced body of data on pulmonary physiology and microstructure: specific ventilation (SV), alveolar partial pressure of oxygen (pAO2), and apparent diffusion coefficient (ADC). The ability to extract all three of these metrics in a single acquisition period over multipe breaths confers several advantages. Most importantly, the use of a multi-breath sequence leads to more physiologically meaningful measurements. The simultaneous technique also results in inherent co-registration of all three parameters. Once the multi-breath HP MRI approach has been optimized, we will use it to study pulmonary function and structure in 120 COPD patients recruited from the Temple cohort of the COPDGene study. This cohort has already been well characterized by CT and spirometry. Our research on these subjects will first focus on correlating HP MRI metrics with these more established techniques. We will then compare HP MRI parameters with CT parameters in terms of their ability to predict whole-lung functional change, exacerbation frequency, and emphysematous remodeling over a two-year follow-up period. The broad impact of this research will be the development of a technique that can simultaneously derive multiple non-invasive markers of obstructive lung disease. These metrics will supply important physiologic data on the development and progression of COPD that will make a valuable contribution to the ongoing effort to better phenotype this protean disease. The parameters will also provide safe and sensitive markers for longitudinal studies of novel COPD therapies.